Actions of opioids on respiratory activity via activation of brainstem mu-, delta- and kappa-receptors; an in vitro study.
Opioid-induced respiratory depression is well documented. However, exact sites of action and mechanisms for opioid-induced effects on respiration have not yet been elucidated. The present study was carried out on isolated brainstem-spinal cord preparations from newborn rats in order to explore the opioid activity on brainstem mu-, delta- and kappa-receptors. The brainstem-spinal cord was isolated from 0- to 4-day-old Sprague-Dawley rats. The preparation was perfused with artificial cerebrospinal fluid (28.5 degrees C) equilibrated with 95% O2 and 5% CO2 at a pH of 7.4. Neuronal respiratory activity was recorded from the ventrolateral part of the medulla oblongata and efferent impulses from C4 or C5 ventral roots. Effects of the mu-receptor agonist DAGO, the delta-receptor agonist DPDPE and the kappa-receptor agonist U50,488 on respiratory frequency (fR), inspiratory time (Ti) and peak integrated C4 amplitude (Int[C4]) were measured. In addition, the effect of pre-treatment with the mu1 receptor antagonist naloxanazine (35 mg/kg, subcutaneous injection) was evaluated. DAGO reduced fR and Ti in a concentration-dependent manner and caused a reduction of Int(C4) at high concentrations (10 microM). The mu1 receptor antagonist naloxanazine shifted the fR concentration-response curve for DAGO to the right (P < 0.05). DPDPE had no effect on respiratory activities whereas U50,488, like DAGO, reduced fR and Int(C4) in a concentration-dependent manner. It was concluded that mu-opioid receptors, including the mu1 were involved in fR reduction whereas kappa-opioid receptors were involved in reduction of both fR and respiratory amplitude. Delta-opioid receptors do not seem to participate in respiratory modulation at this age.
Takita
K
K
Department of Anesthesiology and Intensive Care, Hokkaido University School of Medicine, Sapporo, Japan.
Herlenius
E A
EA
Lindahl
S G
SG
Yamamoto
Y
Y
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D008526:Medulla Oblongata / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012137:Respiratory System / Q000187:drug effects*
D004745:Enkephalins; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-